1. Field of the Invention
The invention relates to substituted isoquinolines, compositions containing the same and methods of using the same to antagonize the effects of platelet activating factor.
2. Description of the Prior Art
Platelet activating factor (PAF) is a mediator of events in the body--an autocoid like histamine, prostaglandins, and the leukotrienes. However, unlike these other substances, PAF is a phospholipid, the first mediator originating from cell membranes to be identified. The structure of PAF is as follows: ##STR1##
PAF is also known by the trivial name pAF-acether, a reference to the acetate group and ether structure which characterize the compound.
PAF is released by a number of different cell types and exerts a vast array of biological activities, including platelet activation/aggregation (the first described property, from which its name derives), bronchoconstriction and increased vascular permeability. Proposed initially as a mediator of inflammation and allergy, but then found to be involved in a number of other conditions ranging from septic shock and early pregnancy to immune regulation, PAF is now considered to be a major agent of cell to cell communication.
Efforts are being directed towards elucidating PAF's role in the many conditions in which it has been implicated, work which has been greatly aided by the synthesis of several specific and chemically unrelated PAF-antagonists. As the evidence for PAF's involvement in a number of conditions slowly accumulates, so the potential therapeutic uses for such compounds are outlined.
These potential indications for PAF-antagonists range from use in asthma and other inflammatory and allergic disorders, to transplant rejection, shock states such as septicaemia, and renal disease. In addition, PAF's involvement in early pregnancy points to new treatments for infertility and new approaches to contraception, while analogues of PAF appear to hold potential for use in cancer and the treatment of hypertension.
The PAF or PAF-acether antagonists which have been developed to date fall principally into four different groups: PAF analogs, which include non-constrained backbone and constrained backbone types, the latter being produced by cyclization of the PAF structural framework; natural products, such as terpenes (e.g., ginkolides), lignans and fungal fermentation products; synthetic compounds, primarily pyrazolo-thiazole analogs; and known pharmacological agents used for other purposes, including triazolobenzodiazepine psychotropic agents and calcium channel blocking agents. The following illustrations of typical prior art PAF antagonists are derived from P. J. Barnes et al., J. Aller. Clin. Immunol., 81(5):919-934 (1988); see also P. Braquet and J. J. Godfroid, Trends in Pharmacological Sciences, 7(10):397-403 (1986): ##STR2##
In addition to the foregoing, a recently developed antagonist of the PAF-analog type, SRI 63-675, is disclosed in D. A. Handley et al., Thrombosis and Haemostatis, 57(2):187-190 (1987), having the following structure: ##STR3##
Certain diketopiperazine derivatives having PAF-inhibiting activity have recently been isolated from microbial sources, including metabolites of a streptomyces bacterium. N. Shimazaki et al., J. Med. Chem., 30:1706-1709 (1987).
New, more effective antagonists of PAF, particularly of the synthetic type, are actively being sought.